The present invention relates to a novel nitroimidazole. derivative which is useful as a diagnostic imaging agent.
In recent years, everyday foods in Japan have been Europeanized or Americanized, and in accordance with this trend, patients suffering diseases of the circulatory system, such as hyperlipidemia, angina pectoris, and myocardial infarction, have been drastically increasing. Such a disease may cause damage to nutrition-supplying organs of the body, such as the heart and blood vessels, and may be life threatening, depending on the progress of the disease. Therefore, the site of the disease must be determined at early stages of the disease and the disease must be subjected to appropriate treatment.
In ischemic diseases, peripheral tissues of ischemic sites are destroyed by active oxygen, and thus it is important not only to find the presence of vasoconstriction sites or heart valve disorder, but also to determine ischemic sites which are generated due to lack of blood flow. Briefly, damaged tissues at such ischemic sites, as well as vasoconstriction sites and cardiac dysfunction, may be life threatening.
In recent years, diseases of circulatory organs have been reliably diagnosed, and the sites of the diseases have been precisely determined through angiography, electrocardiogram, load electrocardiogram, or 24-hour monitoring. However, even when such a method is employed, ischemic sites or tissues cannot be detected directly, and biopsy has been the main means for detecting damage derived from ischemia. Therefore, there has been demand for means to determine ischemic sites conveniently and reliably.
Meanwhile, in treatment of cancer, it is important to detect the presence of cancer cells at early stages of tumor formation, in order to enhance the effect of chemotherapy or radiotherapy or to arrest the progress of cancer, such as by preventing metastasis. In recent years, it has been reported that, among cancer cells, there are hypoxic cells which are resistant to a chemotherapeutic agent or radiation. Therefore, the amount of such hypoxic cells and the position at which the cells exist must be detected, and then the cells must be eliminated.
Conventionally, a method in which a monoclonal antibody against a tumor marker is employed is known as a typical method for detecting and identifying cancer cells. However, in the method, although the presence or the amount of a tumor maker is determined, the position at which the marker is present cannot be detected.
In order to detect the position at which a tumor is present, there has been carried out an imaging method, such as magnetic resonance imaging (MRI) in which the distribution of water is determined through proton NMR, or X-ray imaging by use of an organic iodine compound. However, such a method is carried out for merely detecting difference in biophysical properties of the tumor, which is attributed to the cancer tissue, and the method does not image cancer cells directly. Therefore, such a method does not provide information about the presence of chemotherapeutic-agent-resistant or radiation-resistant cells, the information being an index of difficulty in treatment of the tumor.
In order to solve the aforementioned problems, an object of the present invention is to provide a compound which is useful for imaging cancer cells or ischemic sites of circulatory organs.
In view of the foregoing, the present inventors have performed extensive studies, and have found that a nitroimidazole derivative represented by the following formula (1) is selectively directed to ischemic sites of circulatory organs, or chemotherapeutic-agent-resistant or radiation-resistant hypoxic cancer cells; and that when the derivative is employed as a contrast medium in diagnostic imaging, the cells can be imaged. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides a nitroimidazole derivative represented by the following formula (1): 
[wherein R1 represents a hydrogen atom or a C1-C4 alkanoyl group, and X represents a fluorine atom or an isotope thereof].
The present invention also provides a diagnostic imaging agent comprising the nitroimidazole derivative (1) as an active ingredient.
The present invention also provides a nitroimidazole derivative represented by the following formula (2): 
[wherein R1 represents a hydrogen atom or a C1-C4 alkanoyl group], and a method for producing the nitroimidazole derivative represented by formula (1), comprising fluorination of the nitroimidazole derivative of formula (2).